Insights on Nefecon®, a Targeted-Release Formulation of Budesonide and Its Selective Immunomodulatory Effects in Patients with IgA Nephropathy

Abstract

Immunoglobulin A nephropathy (IgAN) is a chronic, immune-mediated kidney disease characterized by the deposition of galactose-deficient immunoglobulin A1 (Gd-IgA1) in the kidneys. Excess Gd-IgA1 production in patients with IgAN is located within the mucosa-associated lymphoid tissue, particularly within the lamina propria in the distal ileum. Nefecon^® is a targeted-release formulation of the corticosteroid budesonide, which became the first treatment approved by the US Food and Drug Administration (FDA; brand name, TARPEYO^®) and European Medicines Agency (EMA; KINPEYGO^®) for patients with primary IgAN at risk of rapid disease progression, after demonstrating clinically significant reduction of proteinuria in an interim analysis of the Phase III NefIgArd trial. After showing a significant reduction in estimated glomerular filtration rate decline in the full 2-year analysis of the trial, Nefecon was granted full approval by the FDA to reduce the loss of kidney function. Nefecon was specifically designed to deliver budesonide to the distal ileum, selectively targeting excess Gd-IgA1 production in the gut-associated lymphoid tissue. In this review, we describe the properties of Nefecon and the evidence to date that confirms its localized treatment effect. We also present unpublished evidence from Phase I trials investigating the pharmacokinetics and cortisol suppression effects of Nefecon in healthy participants. These studies demonstrated that Nefecon has a distinct pharmacokinetic profile from other budesonide products, allowing for targeted, localized action in the distal ileum. When considered alongside existing clinical trial data showing the effect of Nefecon on gut-associated biomarkers, available evidence indicates that Nefecon has a selective immunomodulatory mechanism of action and a direct disease-modifying effect in patients with IgAN, while having low systemic exposure and adverse effects.

Keywords: GALT; biomarkers; drug delivery; pharmacokinetics.

Figure 1

Targeting mucosal IgA synthesis in the GALT. Image on the left is adapted from Kidney Int, volume 81(9), Boyd JK, Cheung CK, Molyneux K, Feehally J, Barratt J. An update on the pathogenesis and treatment of IgA nephropathy. 833–843, Copyright 2012, with permission from Elsevier and image on the right is adapted from Kidney Int Rep, volume 5(10), Barratt J, Rovin BH, Cattran D, Trimarchi H, Zhang H. Why target the gut to treat IgA nephropathy? 1620–1624, Copyright 2020, with permission from Elsevier.

Figure 2

Effect of Nefecon 16 mg/d on eGFR and UPCR in the NefIgArd trial.

Figure 3

Schematic image of Nefecon.

Figure 4

Arithmetic mean budesonide concentration with 90% CIs over time in the NEF-101 study.

Figure 5

Geometric mean budesonide concentration over time in the NEF-105 study; (A) linear concentration axis and (B) logarithmic concentration axis.

Figure 6

In vitro budesonide release profiles using the biorelevant method. Adapted with permission from Dressman J, Philipson R, Barratt J. Comparison of the dissolution profile of Nefecon with three other commercially available oral formulations of budesonide: Implications for interchangeability. IIgANN, Tokyo, Japan, 2023.

Figure 7

Biomarker assessments from the Phase IIb NEFIGAN trial with significant changes from baseline at 9 months for Nefecon 16 mg vs standard of care, as measured by FDR q-value. Adapted from Kidney Int, volume 105(2), Wimbury D, Muto M, Bhachu JS, et al. Targeted-release budesonide modifies key pathogenic biomarkers in immunoglobulin A nephropathy: insights from the NEFIGAN trial. 381–388, Copyright 2023. Creative Commons.